The present invention is concerned with an improved process for forming a single composition from two antibiotics, e.g., from Quinolone antibiotics and Beta-lactam antibiotics, as Penicillin and Cephalosporin types, and also with the addition of steps to add a third antibiotic component to the bi-component composition, the third (3rd) antibiotic drawn from the group Vancomycin, Erythromycin, Azithromycin, an Aminoglycoside as Gentamycin, A Tetracycline, Clindamycin, and Chloramphenicol.
The value of a composition wherein a trio of individual antibiotics are joined is that the bacterial infective agent will simultaneously be attacked by agents which are known to attack the cell-wall producing enzyme of the bacteria, and inhibit the DNA gyrase enzyme, and inhibit the enzyme that controls bacterial protein synthesis.
The value of this composition of three antibiotic functional types is that it will further be seen that resistant strains will be very unlikely to develop due to the necessity of simultaneously overcoming three attacking agents.
There is evidence for this statement in the present day success of several cocktailsxe2x80x94combinationsxe2x80x94of drugs which are being utilized to treat AIDS patients, TB patients and other similar examples. In the case of the AIDS virus, a combination of two retroviral inhibitors, as AZT and DDI are being employed plus one of several viral protease inhibitors as invirase. In the case of TB patients a cocktail of four drugs is being utilized successfully to overcome resistant TB strains. Further, White, U.S. Pat. No. 5,281,703, has shown that a composition containing a Cephalosporin and a Quinolone antibiotic is very effective in treating certain pneumonias. Pirie, U.S. Pat. No. 4,351,840, has also shown that the composition of a Penicillin with a Beta-lactam protective inhibitor enhances the value of Penicillin.
In U.S. Pat. No. 5,693,791, whose disclosure is incorporated by reference herein, I have disclosed the process of linking a wide variety of antibiotic moieties, two at a time, using diisocyanates, dianhydrides, diacid chlorides, diepoxides, carbodiiamides and the like as the linking reagents.
There are prior for linking two antibiotics into a single composition, e.g., quinolone antibiotics with the beta-lactam, cephalosporin. However, the processes are complex: the reagents are dangerous; and they are all expensive. They are compared in the following table:
1. White, Norwich Eaton Pharmaceutical, U.S. Pat. No. 5,180,719
A. Links quiniolines and cephalosporins
B. Linking agent-phosgene
C. Synthesis stepsxe2x80x94multiple
D. Activityxe2x80x94good, human tests
E. Costxe2x80x94high
2. Albrecht, Hoffman-LaRoche, U.S. Pat. No. 5,336,768
A. Links quinolones and cephalosporins
B. Linking agentxe2x80x94phosgene
C. Synthesis stepsxe2x80x94multiple
D. Activityxe2x80x94good, human tests
E. Costxe2x80x94high
3. Machida, Eisai (Japan), U.S. Pat. No. 4,546,176
A. Links cephalosporin with substituted quinolone nucleus (not quinolone antibiotic)
B. Linking agentxe2x80x94acid chloride of quinolone
C. Synthesisxe2x80x94multi-step
D. Activityxe2x80x94good
E. Costxe2x80x94high
4. Arnold, ICI, U.S. Pat. No. 5,232,918
A. Links cephalosporin with substituted quinolone nucleus (not quinolone antibiotic)
B. Linking agentxe2x80x94acid chloride of quiniolone
C. Synthesisxe2x80x94multi-step
D. Activityxe2x80x94good
E. Costxe2x80x94high
5. Haskell, Warner-Lambert, U.S. Pat. No. 4,404,201
A. Links cephalosporin-quinolone nucleus (not quinolone antibiotic)
B. Linking agentxe2x80x94imidazole
C. Synthesis stepsxe2x80x94multiple
D. Activityxe2x80x94good
E. Costxe2x80x94high
For example, the fluoroquinolone antibiotic inhibits DNA synthesis in the bacteria; Cell wall synthesis is inhibited by the beta lactam antibiotic; and protein synthesis of the bacterial cell is stopped by a wide variety of antibiotics, e.g., tetracyclines, metronidazole, chloramphenicol, clindinomycin, aminoglycosides, erythromycin, azithromycin and vancomycin. The last named, vancomycin, is also a cell wall synthesis inhibitor and has been the antibiotic of choice in attacking staphylococcus infections.
There are a number of classes of antibiotics which may be designated xe2x80x9cbeta-lactams.xe2x80x9d
1. Penicillins
2. Cephalosporins
3. Monobactams
4. Carbapenems
All four classes of beta-lactams process several features in common:
1. a 4-membered ring termed a xcex2-lactam ring. This ring is chemically sensitive to acid and to some bacterial enzymes.
2. Three of the four types have a ring fused to the xcex2-lactam ring, but not the monobactam type.
3. All possess a carboxyl group pendant to the ring fused to the xcex2-lactam ring, or a carboxyl group on a side chain pendant to the xcex2-lactam ring.
4. All possess an amino or hydroxyl group on the pendant side chain of the xcex2-lactam ring.
From a microbial point of view all four classes of xcex2-lactams interfere with cell wall synthesis of bacteria.
These four classes of antibiotics have been designated as xe2x80x9cbeta-lactamsxe2x80x9d in modern pharmacology books. See, for example, pages 724-737 of Chapter 43 in xe2x80x9cBasic and Clinical Pharmacology,xe2x80x9d B. G. Katzung, Appleton and Lange, 7th edition, 1998, Stamford, Conn.
The general formula for the three antibiotic species is given below 
in which Q is a Quinolone antibiotic joined to a Beta-lactam antibiotic B by means of an amide group, or an ester group, and the Beta-lactam antibiotic is then joined by means of a linkage. 
in which Z is an oxygen or a nitrogen atom, and A is an antibiotic drawn from the following group:
1. Tetracyclines (all)
2. Metroindazole
3. Chloramphenicol
4. Clindinamycin
5. Aminoglycosides (all)
6. Erythromycin
7. Azithromycin
8. Vancomycin
The initial step in these syntheses is the conversion of the Quinolone to an acid chloride by means of reaction with thionyl chloride. The second step is the reaction of the Quinolone acid chloride with a Beta-lactam type bearing an amino group. The third step is the conversion of the carboxyl group of the Beta-lactam molecule to an acid chloride utilizing the reagent triphenyl phosphine and carbon tetrachloride. The fourth step in the reaction sequence is the reaction of the Beta-lactam acid chloride with the third component drawn from the list of eight antibiotics above, which forms with an amide linkage or an ester linkage.
The three-component antibiotic produced is suitable for the treatment of a wide variety of bacterial infections in man and animals, and will reduce substantially the possibility that antibiotic resistant strains of bacteria will develop.
It will be noted that the chemistry has been selected to avoid structural changes in the components, and chirality is also maintained.
The synthesis of the general formula 
for the antibiotic composition is detailed below, in which Qxe2x80x94is a quinolone, Bxe2x80x94is a Beta-lactam, Zxe2x80x94is an oxygen or nitrogen and A is a third component, an antibiotic.
The initial step is the conversion of a Quinolone to the corresponding acid chloride 
in which R is an alkyl group and Y is an amine substituted group without a free amine group
Ofloxacin 
and Nalidixic Acid 
and Pefloxacin 
are example Quinolone antibiotics.
The conversion to the corresponding acid chlorides is straightforward and utilizes SOCl2. 
There are no isomers resulting from this reaction, the product is a singular one immediately useful in the synthesis sequence.
The reaction with nalidixic acid, or Ofloxacin is analgous to the Pefloxacin reaction, when thionyl chloride is the reagent for conversion to the acid chloride.
The presence of the quinolone component inhibits the DNA gyrase enzyme essential to bacterial multiplication.
The second step in the synthesis sequence is the condensation of the Quinolone acid chloride with the Beta-lactam type antibiotic. The purpose of this component is to cause inhibition of the cell wall synthesis by bacteria.
The following penicillins will be employed: 
in which R is: 
The following Cephalosporins will be employed: 
wherein R1 and R2 are as listed,
The following miscellaneous types:
Carbapenems 
Monobactam 
The coupling of component 1, the Quinolone acid chloride with the componene 2, the Beta-lactam and related components gives the general formula 
in which Q is the acid chloride which interacts with an amino group on the Beta-lactam or related structure, to give an amide, or reacts with an hydroxyl group on the Beta-lactam or related structure to give an ester. The reaction is conducted in pyridine, the presence of which maintains a medium in which the Beta lactam structure is stable.
An example typical of the amide type formation is given below:
General Formula 
Specific example:
The condensation of a quinolone acid chloride, nalidixic acid chloride with ampicillin 
At the conclusion of the reaction the HCl is neutralized by the addition of the stoichometric quantity of sodium bicarbonate. (See Experimental for details).
The reactions with all Quinolone acid chlorides with the Beta Lactams and related carbapenems, and monobactams are conducted in analogous fashion.
A specific example of the condensation of a Quinolone acid chloride with an amino group bearing Beta-lactam or related carbapenems or monobactam is given below: 
The coupling of the third component to the first two is further accomplished as described below.
The general formula for the product is 
in which Q is a Quinolone, Z is Oxygen (as in an ester) or N (as in an amide), B is a Beta-lactam or monobactam, or carbapenem, and A is an antibiotic drawn from the list noted above in the xe2x80x9cSummary of the Inventionxe2x80x9d and also below.
xe2x80x9cAxe2x80x9d List
1. Tetracyclinesxe2x80x94(all)
2. Metronidazole
3. Chloramphenicol
4. Clindinamycin
5. Aminoglycosidesxe2x80x94(all)
6. Erythromycin
7. Azithromycin
8. Vancomycin
The initial step in the addition of the third component is the conversion of the first two components, synthesized above, to an acid chloride utilizing an unusual reaction of carboxyl groups with triphenylphosphine and carbon tetrachloride which does not generate acid which would destabilize the Beta-lactam type structures. 
An example of the reaction is, 
All quinolones (listed above Ofloxacin, and nalidixic acid and pefloxacin) and the xcex2-Lactam and related structures and their condensation products react in analogous fashion with triphenyl phosphine and carbon tetrachloride in order to form the acid chloride.
The coupling of the third component to the acid chloride formed of the two components, just described above, is carried out in pyridine solution with the antibiotics in the xe2x80x9cAxe2x80x9d as below:
1. Tetracycline
Doxycycline will be utilized to demonstrate coupling to the xe2x80x9ctwo componentxe2x80x9d acid chloride, but all generic tetracyclines may be utilized. 
The phenolic group is the most neucleophilic group in the tetracycline molecule and will be preferentially attacked by the acid chloride.
Chlortetracycline, oxytetracycline, tetracycline, demeclocycline, methacycline and minocycline will react with the xe2x80x9c2-compositionxe2x80x9d acid chloride in the analagous fashion.
2. Metronidazole
The acid chloride resulting from the condensation of pefloxacin and ampicillin followed by reaction with triphenylphosphine and carbon tetrachloride reacts with metronidazole as follows: 
The hydroxy ethyl group of the imidazole is attacked by the acid chloride to form the ester.
3. Chloramphenicol
The acid chloride, resulting from the condensation of pefloxacin and ampicillin, followed by the reaction with triphenylphosphine and carbon tetrachloride, reacts with chloramphenicol as follows: 
4. Clindinamycin
Clindinamycin is one of the few antibiotics which are effective against anaerobic infections and is used particularly with gentamycin for belly wounds and septic abortions.
The acid chloride resulting from the condensation of pefloxacin and ampicillin, followed by the reaction with triphenylphosphine and carbon tetrachloride reacts with clindinamycin as follows, the secondary hydroxyl adjacent to the Sxe2x80x94CH3 group on the ring being the most neucleophilic. 
5. Aminoglycosides
The aminoglycoside example utilized will be gentamycin C1, but gentamycin C2, gentamycin C1, kanamycin, amikacin and tobramycin will react analogously in the coupling scheme outlined below. For the example, gentamycin C2 will be utilized.
The acid chloride resulting from the condensation of pefloxacin and ampicillin followed by reaction with triphenylphosphine and carbon tetrachloride reacts with gentamycin C1, as follows: 
All of the primary amino groups are essentially equivalent chemically, thus all three can be seen as yielding clinically essentially the same product. It is also true that gentamycins, tobramycin, and netilimicin gave clinically similar results as well as amikacin and kanamycin.
6. Erythromycinxe2x80x94A Macrolide
The acid chloride resulting from the condensation of pefloxacin acid chloride and ampicillin, followed by the reaction with triphenylphosphine and carbon tetrachloride, reacts with erythromycin as follows: 
7. Azithromycinxe2x80x94a macrolide
The condensation of the acid chloride Formula I with Azithromycin takes place as follows to give the trio of antibiotics, into a single composition: 
8. Vancomycin
The condensation of the acid chloride Formula I with Vancomycin takes place as below to give the antibiotics into a single composition. The free amino group is the most neucleophilic group and reacts with the acid chloride (Formula I) preferentially. 
Procedure Axe2x80x94Conversion of Quinolones to Acid Chlorides
The conversion of all quinolone compounds possessing a free carboxyl group, but not a free amino group, is carried out by using an excess of thionyl chloride as the reactive agent by the procedure according to Shriner, et al, The Systematic Identification of Organic Compounds, John Wiley, 1948. To 0.01 mole of the quinolone acid is added 5 ml of thionyl chloride and the reaction is carried out in a 50 ml RB flask equipped with a reflux condenser, stirrer and thermometer and heating mantle and the reaction maintained at 50xc2x0 C. for 4 hours, or until the evolution of SO2 and HCl ceases.
The reaction product is obtained by evaporating the liquid solution to dryness at reduced pressure at 0xc2x0 C. At all times the product must be protected from moisture. The residue product is retained for the next reaction in the sequence, the reaction of the quinolone acid chloride with the Beta-lactam type antibiotic, i.e. the penicillin, cephalosporin, carbapenem or monobactam.
Procedure Bxe2x80x94The Condensation of a Quinolone Acid Chloride with a Beta Lactam, Carbapenem, or Monobactam (all of which possess a pendant amino or hydroxyl group.
The reactions are all conducted at the 0.01 mole scale, employing the product of reaction of xe2x80x9cAxe2x80x9d above. The residue from reaction xe2x80x9cAxe2x80x9d above is taken up in 25 ml of dry pyridine in a 50 ml RB flask equipped with stirrer, thermometer and a means of heating and or cooling.